Risk-adapted procedures for HSCT from alternative donor in ... - Nature

Bone Marrow Transplantation (2008) 42, S97–S100 & 2008 Macmillan Publishers Limited All rights reserved 0268-3369/08 $32.00

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REVIEW

Risk-adapted procedures for HSCT from alternative donor in children with severe aplastic anaemia M Fu¨hrer Department of Haematology, Oncology and Bone Marrow Transplantation, Dr von Haunersches Kinderspital, Ludwig-Maximilians University of Munich, Munich, Germany

The outcome of haematopoietic SCT (HSCT) from matched unrelated donors in children with severe aplastic anaemia (SAA) has improved significantly in the last decade and should be offered to all children who fail to respond to their first course of combined immunosuppressive therapy. High-resolution typing for HLA class I and II is mandatory for donor selection. In 10/10 or 9/10 alleles matched donors, a non-TBI conditioning based on fludarabine, CY and anti-thymocyte globulin is sufficient to allow for sustained engraftment when unmanipulated BM is used. Owing to increased rates of cGVHD after PBSC transplantation are reported in young patients, BM is the preferred stem cell source. HSCT from mismatched related and unrelated donors are still high-risk procedures. New techniques for graft manipulation such as CD3/CD19 depletion might improve engraftment and immune reconstitution. In T-cell depleted grafts, irradiation-based conditioning seems to be inevitable to reduce the high risk for rejection. Bone Marrow Transplantation (2008) 42, S97–S100; doi:10.1038/bmt.2008.293 Keywords: severe aplastic anaemia in childhood; HSCT in SAA in children; BMT in SAA in children; matched unrelated donor SCT in SAA in children; alternative donor in SAA in children

40% of responders never reach normal blood counts.1 This phenomenon might be caused by exhaustion of the stem cell pool or by an insufficiently controlled autoimmune attack against stem and progenitor cells. The relatively high incidence of relapse in children treated with IST and the reported rate of CsA dependency seem to strengthen the theory of an ongoing immune attack. However, both stem cell exhaustion and a chronically destructive environment can result in increased proliferative stress for the residual stem cells, and this might promote clonal progression.5 Haematopoietic SCT (HSCT) in children with SAA bears certain challenges. First, non-engraftment and graft rejection still constitute a significant problem. Donor T cells are of significant relevance for sustained engraftment, and thus T-cell depletion enhances the risk for non-engraftment. In contrast to patients with malignant diseases, there is no benefit of GVHD, especially chronic GVHD (cGVHD) for SAA patients. Thus, especially in children, any effort should be made to avoid cGVHD. In a paediatric cohort also, the risk of long-term sequelae being considered and irradiationbased regimen should be replaced wherever possible.

Aims The aim of this review is to describe

Introduction In children with severe aplastic anaemia (SAA) lacking an HLA-identical sibling donor, combined immunosuppressive therapy (IST) is the treatment of first choice. In several trials, response rates of 60–80% and survival rates of 80–90% have been published.1–3 However, a significant proportion fails to respond to a first course of IST, and data from Japan showed a much inferior chance to respond to a second course of IST in children as compared with adults.4 Approximately

indications for HSCT from an alternative donor in children with SAA risk factors that might influence the outcome of HSCT in this patient group strategies to adapt the procedure to the individual risk profile to improve survival. The impact of HSCT on the health-related quality of life is of great importance in a paediatric population with a non-malignant disease. Therefore, one focus of this review lies on long-term sequelae, especially cGVHD and the risk of secondary malignancies.

Materials and methods Correspondence: Dr M Fu¨hrer, Department of Haematology, Oncology and Bone Marrow Transplantation, Dr von Haunersches Kinderspital, Ludwig-Maximilians University of Munich, Lindwurmstr. 4, 80337 Mu¨nchen, Germany. E-mail: [email protected]

This review is based on the analysis of long-term outcome of the cohort of the prospective multicentre trial of the German/Austrian Aplastic

HSCT from alternative donor in children with SAA M Fu¨hrer

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Anemia Working Group (recent analysis, unpublished data) to define the indication for second-line HSCT data published between 2000 and 2008 on alternative donor transplantation in children data published on alternative donor transplantation in age-mixed cohorts.

Indication for alternative donor transplantation In children with an HLA-identical sibling donor, immediate BMT is the treatment of first choice.6 However, most paediatric patients with SAA lack a matched sibling donor. Especially in the former high-risk group of vSAA (very severe aplastic anaemia) patients (o200 granulocytes/ml), response rates and survival after IST are in the range of survival rates after BMT.1 Thus, HSCT from alternative donors cannot be recommended for front-line therapy. However, in both the German and the Japanese multicentre trials for IST, a very small subgroup of patients who did not respond with their granulocyte counts (o500/ml at day 112 after initiation of IST) showed a very high risk for early death.2 For IST non-responders, Kosaka et al.4 could show that in children, HSCT from an alternative donor is superior to a second course of IST (survival 5 years after initiation of second-line therapy 83.9 vs 9.5%, P ¼ 0.001). There are still only very few data on long-term outcome in children who responded to front-line treatment with IST. The cohort (n ¼ 146) of the prospective multicentre trial of the German/Austrian Aplastic Anemia Working Group1 was re-analysed for long-term outcome in February 2008. After a median follow-up of 8.5 years, survival after IST is still superior in vSAA patients (granulocytes o200/ml) when compared with SAA patients (92 vs 65%; P ¼ 0.01). There was no difference in long-term outcome between fast (o3 months) or slow responders (up to 1 year); however, the quality of response had a clear impact on survival with 99% in CR and 81% in PR. Time from diagnosis (41 year)7–9 and pretreatment with IST6 seem to negatively affect the prognosis after HSCT. Donor selection The significant improvement in outcome after matched unrelated donor (MUD) transplants in the last decade is thought to be mainly related to the introduction of HLA high-resolution typing resulting in less graft failure and less acute GVHD (aGVHD) and cGVHD.3,10 Several reports could demonstrate a significantly better survival in patients grafted from a donor with a better HLA match; however, in these reports, only DRB1 was tested on the molecular level.7,9 The effect of mismatch seems to be less prominent in children or in certain ethnicities11 and can be modulated by serotherapy (anti-thymocyte globulin or campath) and graft manipulation (T-cell depletion). Besides HLAmatching, sex mismatch also seems to affect both the risk of GVHD and rejection.12 Graft source and manipulation In recent years, the use of PBSC has increased continuously. In a joint analysis of data from the European Group for Blood and Marrow Transplantation (EBMT) and the Center of International Blood and Marrow Transplant Bone Marrow Transplantation

Research (CIBMTR) in patients who received their first allograft for SAA from an HLA-matched sibling, donor survival in young patients o20 years was inferior after PBSC transplantation (73%) when compared with BMT (85%). This was because of a significantly increased rate in cGVHD. Although the higher content of stem and progenitor cells resulted in faster recovery of haematopoiesis, the incidence of primary and secondary graft failure was similar between BM and PBSC.13 The data on transplants using unrelated cord blood is inconclusive. The incidence of transplant-related events after MUD-cord blood is reported to be higher in SAA and Fanconi anaemia when compared with other diseases.14 Cell content seems to be especially crucial in SAA. In contrast to patients with malignant diseases, patients with SAA do not profit from GVHD. However, because of the high risk of graft failure and early and late rejection in SAA,15 T-cell depletion was not implemented in most of the transplant protocols for SAA. In IST refractory patients lacking an HLA-matched donor, large doses of highly purified CD34 þ -selected haematopoietic stem cells from alternative donors were transplanted successfully after an intensified immunablative conditioning regimen.16,17

Conditioning regimen There are only a few publications on childhood alternative donor transplants in SAA, and most cohorts are very small. Kojima et al.18 reported on 15 children grafted with unmanipulated marrow from serologically matched unrelated donor after conditioning with CY, anti-thymocyte globulin and TBI 5 Gy. GVHD prophylaxis consisted of CsA or tacrolimus and MTX. All patients engrafted and were alive after a median follow-up of 51 months. Onethird of the patients developed aGVHD grade I–III, and one patient developed cGVHD. Vassiliou et al.19 successfully grafted seven patients (median age 8 years) with unmanipulated marrow after conditioning with TBI 3 Gy (single dose), CY and Campath-1G. Donors were HLAmatched (A, B and C serologically or low resolution and DRB1 and DQB1 high-resolution typing) unrelated in six patients with a haploidentical sister in one patient. All but one patient had previously received IST. GVHD prophylaxis consisted only of CsA. All patients achieved full donor engraftment with minimal acute toxicity, no grade III–IV aGVHD and no cGVHD. Relapse-free survival was 100% at a median follow-up of 32 months. Chan et al.20 used a fludarabine-based conditioning (plus CY and ATG) to graft five children (median age 3 years) from one Ag mismatched relatives (n ¼ 3) or matched unrelated donors (n ¼ 2). All patients achieved complete sustained donor engraftment; however, two patients developed grade III aGVHD followed by extensive cGVHD. Bunin et al.21 achieved successful engraftment in 12/12 paediatric patients (median age 6 years) after transplantation of partial T-cell depleted BM from matched (n ¼ 4), one Ag (n ¼ 6) or two Ag (n ¼ 2) mismatched unrelated donors. Conditioning regimen consisted of TBI 12–13.2 Gy, CY and Ara-C or thiotepa. Nine of twelve patients are alive 13–153 months after transplant. aGVHD grade III occurred in one patient and cGVHD in two. Benesch et al.16 and Woodard et al.17


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report on successful transplants with large doses of CD34 þ selected stem cells from mismatched related and, matched and mismatched unrelated donors. All patients suffered from IST refractory SAA. Conditioning regimen was on the basis of CY and serotherapy (ATG and/or OKT-3) in combination with TLI/TBI, fludarabine and other agents (thiotepa, BU). Ten of twelve patients survived in good clinical condition, one died from extensive cGVHD15 and one from CMV pneumonitis.17 Deeg et al.8 conducted a dose de-escalating study to determine the minimum effective dose of TBI to achieve sustained engraftment in a cohort of 50 heavily transfused and pretreated (median of four IST courses) SAA patients. A dose of 2 Gy TBI in combination with CY and ATG was shown to be sufficiently immunosuppressive for patients with an HLA-A, B and DR (serological typing)-matched unrelated donor. Bacigalupo et al.22 achieved an actuarial 2-year survival of 73% in 38 children and young adults (median age 14 years) after conditioning treatment with fludarabine, low-dose CY (1200 mg/m2) and antithymocyte globulin using unmanipulated BM as the stem cell source. Younger patients (o14 years; n ¼ 19) showed a lower risk of rejection (5%) and a better survival of 84%. aGVHD grade II–III was documented in 11% and cGVHD in 27% of all patients.

Late effects In a cohort of 37 children and young adults who have been grafted for SAA after an irradiation-based conditioning regimen, there was no difference in self-rating of health status when compared with controls, although patients reported on the expected late effects as there are cataracts, hypothyroidism, short stature in men and gonadal dysfunction.23 Socie et al.24 reported a cumulative incidence of 3.1% for solid tumours in a large cohort of 748 patients who received BMT for SAA. The main risk factors were age (relative risk 1.11 per year) and an irradiation-based conditioning (relative risk 9.56). In patients grafted from identical siblings, the use of total abdominal irradiation and cGVHD were associated with lower survival. In this cohort, total abdominal irradiation was the only factor that was associated with cGVHD. The authors, therefore, recommend avoiding irradiation in the conditioning regimen for sibling transplants in SAA.25

an optimal donor is available. Further analysis of data on long-term outcome after IST is carried out to better describe risk factors for refractory relapse or clonal progression in IST partial responders. Donor selection on the basis of high-resolution HLA typing is strongly advocated. In patients with a 10/10 or 9/10 matched unrelated donor who is willing to donate BM, a non-TBI conditioning regimen on the basis of fludarabine, CY and serotherapy seems to be sufficient to allow for sustained engraftment. GVHD prophylaxis should consist of CsA or Tacrolimus and MTX. The use of BM as a stem cell source is strongly recommended. Transplants from mismatched related or unrelated donors should still be considered experimental. Recent progress in graft manipulation such as CD3/CD19 depletion seems to reduce the risk of graft rejection and infection by accelerating immune reconstitution. However, when T-cell depleted grafts are used, intensified conditioning with TBI or TLI (5–7.5 Gy) seems to be necessary to achieve engraftment.

Conclusions There are still insufficient data on alternative donor transplants in children with IST refractory SAA. International collaborative protocols on donor selection, conditioning, stem cell source, graft manipulation and GVHD prophylaxis are necessary to establish evidence in transplant procedures in this small group of patients. The European working group EWOG-SAA was founded in 2007 as a platform to perform cooperative studies in childhood SAA and to facilitate international cooperation in this field.

Acknowledgements I want to thank Charlotte Niemeyer and her team of EWOGMDS for their support.

Conflict of interest Monica Fuhrer has received lecture fees from an unnamed source. M Fuhrer is also negotiating with Genzyme to support an international study in immunosuppressive therapy in SAA in children.

Discussion The results in matched unrelated donor transplants have improved significantly during the last decade. Thus, this procedure should be offered to all children who are refractory to a first course of IST. Time since diagnosis had a clear impact on rejection and mortality. Therefore, children without a granulocyte response after 4 months should be offered a transplant as soon as possible. All other IST nonresponders should be grafted after 6 months if a well-matched donor (10/10 or 9/10) is available. As we know about the less favourable prognosis in children who achieve only partial response to IST after 1 year, a transplant should also be considered in this group if

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